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Serzan et al. J Cancer Metastasis Treat 2021;7:39 https://dx.doi.org/10.20517/2394-4722.2021.76 Page 5 of 19

Antiangiogenic therapy with TKI greatly improved outcomes for patients with metastatic ccRCC relative to
cytokine-based therapies. Despite consistent improvements in ORR and PFS, these regimens were not
curative. Patients inevitably experienced progression of disease necessitating sequential switching to a
different therapy, often another VEGFR TKI or an mTOR inhibitor. These successive agents increased the
cumulative incidence of off-target adverse effects, which impacted quality of life and contributed substantial
financial toxicity over time. As such, the current role of antiangiogenic TKI monotherapy is limited to
patients who cannot receive ICI therapy due to active autoimmune disease or high dose steroids for central
nervous system metastases.

Immune checkpoint inhibitor therapies
Initial evidence of immunogenicity in RCC was demonstrated in cytokine-based therapies with high dose
interleukin 2 and IFNα, which showed durable, complete responses in small subsets of patients [34,35] . The
ability to induce an adaptive immune response relies on several aspects including tumor antigenicity, extent
[36]
of immune cell infiltrate and immunomodulatory aspects within the tumor microenvironment . ccRCC
tumors are characterized by rich leukocyte infiltrates of CD8+ and CD4+ T cells as well as myeloid derived
[37]
macrophages and neutrophils . Tumors with an abundance of myeloid derived suppressor cells (MDSC)
and polymorphonuclear leukocytes have been associated with higher tumor grade and shorter overall
[38]
survival .
Checkpoint inhibitors are monoclonal antibodies that block physiologic or tumor cell mediated modulation
[39]
of cellular immunity thereby restoring antigen specific cytotoxic T cell-mediated immune response . Two
critical checkpoints include interactions between CTLA receptor and its ligands CD80/86 on antigen
presenting cells typically in peripheral immune organs and the PD-1 receptor and its ligands PD-L1/L2 in
the tumor microenvironment. CTLA-4 binding to its ligand CD80/86 inhibits T cell activation. Therapeutic
inhibition of this interaction with the CTLA-4 inhibitor ipilimumab leads to augmentation of T cell
[40]
activation and proliferation of T cell subsets . In the tumor microenvironment, tumor and immune cells
can upregulate PD-L1/L2 ligands that bind the PD-1 receptor on tumor reactive T cells leading to
[41]
suppression of T cell activity . Inhibition of this interaction with PD-1 antibodies (nivolumab,
pembrolizumab) or PD-L1 antibodies (avelumab, atezolizumab) restores cytotoxic T cell activity and helper
T cell cytokine production.

Nivolumab was the first ICI to show benefit in patients with advanced RCC. Nivolumab was compared to
everolimus in patients who had exhibited disease progression on antiangiogenic therapy and showed
[15]
improved ORR 25% vs. 5% and OS 25.0 months vs. 19.6 months (HR = 0.73; 0.57-0.93; P = 0.002) . Activity
relative to everolimus was particularly apparent in the MSKCC poor risk population (HR death = 0.47; 0.30-
0.73). Although these results were sufficient to confer FDA approval for nivolumab monotherapy, the
efficacy was felt to be insufficient to be superior to VEGFR TKIs in treatment naïve patients. However, the
Checkmate 016 trial explored the combination of nivolumab and ipilimumab in patients with either
treatment naïve or VEGFR TKI resistant ccRCC and showed higher ORR (40.4%) and median PFS (7.7
months) than had been observed with nivolumab monotherapy in the CM 025 trial suggesting it was more
efficacious .
[42]

As a consequence, combination nivolumab and ipilimumab was compared to sunitinib in treatment naïve
patients in the Checkmate 214 phase 3 trial with co-primary endpoints OS, PFS, and ORR in the
intermediate/poor risk disease groups . The study initially met two of three primary endpoints in its target
[17]
population at median follow up 25.2 months. The combination demonstrated improved OS (HR death =
0.63; P < 0.001), ORR 42% vs. 27% (P < 0.001), and complete response rate 9% vs. 1% relative to sunitinib